Non-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs, are drugs with analgesic, antipyretic and anti-inflammatory effects. As analgesics, NSAIDs are unusual in that they are non-narcotic. NSAIDs are sometimes also referred to as non-steroidal anti-inflammatory agents/analgesics (NSAIAs) or non-steroidal anti-inflammatory medicines (NSAIMs). The most prominent members of this group of drugs are aspirin and ibuprofen. Paracetamol (acetaminophen) has negligible anti-inflammatory activity, and is strictly speaking not an NSAID.
The exact mechanism of action of paracetamol is uncertain, but it appears to be acting on the central nervous system. Aspirin and the other NSAIDs inhibit cyclooxygenase, leading to a decrease in prostaglandin production; this reduces pain and also inflammation (in contrast to paracetamol and opioids).
NSAIDs can be broadly classified based on their chemical structure. NSAIDs within a group will tend to have similar characteristics and tolerability. There is little difference in clinical efficacy between the NSAIDs when used at equivalent doses. Rather, differences between compounds tended to be with regards to dosing regimens (related to the compound's elimination half-life), route of administration, and tolerability profile.
Salicylates include: Aspirin, Amoxiprin, Benorilate, Choline magnesium salicylate, Diflunisal, Faislamine, Methyl salicylate, Magnesium Salicylate and Salicyl salicylate (salsalate). Arylalkanoic acids include: Diclofenac, Aceclofenac, Acemetacin, Bromfenac, Etodolac, Indometacin, Nabumetone, Sulindac and Tolmetin. 2-Arylpropionic acids (profens) include: Ibuprofen, Carprofen, Fenbufen, Fenoprofen, Flurbiprofen, Ketoprofen, Ketorolac, Loxoprofen, Naproxen, Tiaprofenic acid and Suprofen. N-Arylanthranilic acids (fenamic acids) include: Mefenamic acid and Meclofenamic acid. Pyrazolidine derivatives include: Phenylbutazone, Azapropazone, Metamizole, Oxyphenbutazone and Sulfinprazone. Oxicams include: Piroxicam, Lornoxicam, Meloxicam and Tenoxicam. COX-2 Inhibitors include: Celecoxib, Etoricoxib, Lumiracoxib, Parecoxib, Rofecoxib and Valdecoxib. Sulphonanilides include Nimesulide and other NSAIDs include Licofelone and Omega-3 Fatty Acids.
Paracetamol and many NSAIDs exhibit low water solubility and are practically insoluble in water. This hinders some aspects of their use for oral administration, including rapidity of action onset.
WO 2004/011537 describes the formation of solid, porous beads comprising a three dimensional open-cell lattice of a water-soluble polymeric material. These are typically “templated” materials formed by the removal of both water and a non-aqueous dispersed phase from a high internal phase emulsion (HIPE) which has a polymer dissolved in the aqueous phase. The beads are formed by dropping the HIPE emulsion into a low temperature fluid such as liquid nitrogen, then freeze-drying the particles formed to remove the bulk of the aqueous phase and the dispersed phase. This leaves behind the polymer in the form of a “skeletal” structure. The beads dissolve rapidly in water and have the remarkable property that a water-insoluble component dispersed in the dispersed phase of the emulsion prior to freezing and drying can also be dispersed in water on solution of the polymer skeleton of the beads.
WO 2005/011636 discloses a non-emulsion based spray drying process for forming “solid amorphous dispersions” of drugs in polymers. In this method a polymer and a low-solubility drug are dissolved in a solvent and spray-dried to form dispersions in which the drug is mostly present in an amorphous form rather than in a crystalline form.
Unpublished co-pending applications (GB 0501835 of 28 Jan. 2005 and GB 0613925 filed on 13 Jul. 2006) describe how materials which will form a nano-dispersion in water can be prepared, preferably by a spray-drying process. In the first of these applications the water insoluble materials is dissolved in the solvent-phase of an emulsion. In the second, the water-insoluble materials are dissolved in a mixed solvent system and co-exist in the same phase as a water-soluble structuring agent. In both cases the liquid is dried above ambient temperature (above 20° C.), such as by spray drying, to produce particles of the structuring agent, as a carrier, with the water-insoluble materials dispersed therein. When these particles are placed in water they dissolve, forming a nano-dispersion of the water-insoluble material with particles typically below 300 nm. This scale is similar to that of virus particles, and the water-insoluble material behaves as though it were in solution.
WO 2007/53197 (Elan Pharma International Ltd) discloses nanoparticulate forms of acetaminophen. Particle sizes of less than 2000 nm are disclosed. The nanoparticulate acetaminophen, or a salt or derivative thereof, compositions can be made using, for example, milling, homogenization, precipitation, freezing, or template emulsion techniques.
In the present application the term “ambient temperature” means 20° C. and all percentages are percentages by weight unless otherwise specified.